The Synthesis of Novel Iodinated Iminodiacetic Acid Analogues as Hepatobiliary Imaging Agents

The synthesis and characterization of N-[2-[[4-iodo-2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(carboxymethyl)glycine and N-[2-[(4-iodo-2,6-diethylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine is presented, as well as a modified and improved synthesis of N-[2-[(2,4-diiodo-6-methylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine. These compounds are new agents for hepatobiliary imaging.     

The Synthesis of Novel Iodinated Iminodiacetic Acid Analogues as Hepatobiliary Imaging Agents

Summary. The synthesis and characterization of N-[2-[[4-iodo-2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(carboxymethyl)glycine and N-[2-[(4-iodo-2,6-diethylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine is presented, as well as a modified and improved synthesis of N-[2-[(2,4-diiodo-6-methylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine. These compounds are new agents for hepatobiliary imaging.     

Synthesis and nmr spectra of the six isomeric thieno[c]-fused 1,7- and 1,8-naphthyridines

Through the use of Pd(0)-catalyzed coupling between 2- and 4-formyl-3-thiopheneboronic acid and 4-iodo-3-aminopyridine ( 1 ) and 3-bromo-2-aminopyridine, convenient one-pot procedures for the preparation of thieno[2,3-c]-1,7-naphthyridine ( 2 ), thieno[3,4-c]-1,7-naphthyridine ( 3 ), thieno[2,3-c]-1,8-naphthyridine ( 6 ) and thieno[3,4-c]-1,8-naphthyridine ( 7 ) have been developed. Thieno[3,2-c]-1,7-naphthyridine ( 4 ) and thieno[3,2-c]-1,8-naphthyridine ( 8 ) were obtained through the coupling of 2-tri-n-butylstannyl-3-thiophenaldehyde with 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide and 3-bromo-2-acetamidopyridine ( 1 ). The yield of 8 was further increased when copper(II) oxide was used as the co-reagent. The ¹³C nmr spectra of the six isomeric thieno[c]-fused 1,7- and 1,6-naphthyridines are discussed.     

4-Substituted 5-nitroisoquinolin-1-ones from intramolecular Pd-catalysed reaction of N-(2-alkenyl)-2-halo-3-nitrobenzamides

4-Methyl- and 4-benzyl-5-aminoisoquinolin-1-ones are close analogues of the water-soluble PARP-1 inhibitor 5-AIQ. Their synthesis was approached through Pd-catalysed cyclisations of N-(2-alkenyl)-2-iodo-3-nitrobenzamides. Reaction of N,N-diallyl-2-iodo-3-nitrobenzamide with Pd(PPh₃)₄ gave a mixture of 2-allyl-4-methyl-5-nitroisoquinolin-1-one and 2-allyl-4-methylene-5-nitro-3,4-dihydroisoquinolin-1-one. N-Benzhydryl-N-cinnamyl-2-iodo-3-nitrobenzamide similarly gave 2-benzhydryl-4-benzyl-5-nitroisoquinolin-1-one and 2-benzhydryl-4-benzylidene-5-nitro-3,4-dihydroisoquinolin-1-one. The isomeric products are not interconvertible. A deuterium-labelling study indicated that the isomers were formed by different pathways: a π-allyl-Pd route and the classical Heck route. The corresponding secondary amides N-allyl-2-iodo-3-nitrobenzamide and N-((substituted)-cinnamyl)-2-iodo-3-nitrobenzamide gave good yields of the required 4-methyl- and 4-((substituted)-benzyl)-5-nitroisoquinolin-1-ones, respectively, under optimised conditions (Pd(PPh₃)₄, Et₃N, Bu₄NCl, 150 °C, rapid heating). Hydrogenation of the nitro groups gave 4-methyl- and 4-benzyl-5-aminoisoquinolin-1-ones, which were potent inhibitors of PARP-1 activity.     

Synthesis, structure, and heck cyclization of the syn- and anti-atropisomers of N-acyl-N-(4-methyl-3,6-dihydro-2H-pyran-3-yl)-2-iodo-4,6-dimethylaniline

The reaction of 2-iodo-2,4-dimethylaniline with 3,4-dibromo-4-methyltetrahydro-2H-pyran, followed by treatment with acetyl bromide or 4-nitrobenzoyl chloride, gave syn- and anti-atropisomers of N-(2-iodo-4,6-dimethylphenyl)-N-(4-methyl-3,6-dihydro-2H-pyran-3-yl)acetamide and N-(2-iodo-4,6-dimethylphenyl)-N-(4-methyl-3,6-dihydro-2H-pyran-3-yl)-4-nitrobenzamide. Heating of the acetamide derivative with palladium(II) acetate in the presence of copper(II) acetate and N,N,N′,N′-tetramethylethane-1,2-diamine resulted in heterocyclization to N-acetyl-4a,6,8-trimethyl-1,4a,9,9a-tetrahydropyrano[3,4-b]indole.     

Reactions of N- and C-Alkenylanilines: III. Synthesis and Cyclization of Substituted 2-(1-Methyl-2-butenyl)anilines

Reactions of substituted 2-(1-methyl-2-butenyl)anilines with iodine result in cyclization and formation of 3-iodo-1,2,3,4-tetrahydroquinolines; N-methylsulfonyl-2-(1-methyl-2-butenyl)anilines give rise exclusively to the corresponding 2-(1-iodoethyl)-3-methyl-2,3-dihydroindoles.     

Reaction of Substituted Methyl 2,3,7-Triazabicyclo[3.3.0]oct-3-ene-4-carboxylates and 1,2,7-Triazaspiro[4.4]non-2-ene-3-carboxylates with Iodinating Agents

Substituted methyl 2,3,7-triazabicyclo[3.3.0]oct-3-ene-4-carboxylates and 1,2,7-triazaspiro[4.4]non-2-ene-3-carboxylates react with N-iodosuccinimide (or the system iodine-silver trifluoroacetate) to give, respectively, methyl 6-iodo-3-azabicyclo[3.1.0]hexane-6-carboxylates or methyl 1-iodo-4,6-dioxo-5-azaspiro[2.4]heptane-1-carboxylates as mixtures of exo and endo isomers.     

Synthesis of 2′-Iodo Analogues of β-Rhodomycins1

Abstract

10-O-(R/S)Tetrahydropyranosyl-β-rhodomycinone (5a,b) was prepared via 7,9-O-phenylboronyl-β-rhodomycinone (3) from β-rhodomycinone (1). Glycosidation of 5a,b with 3,4-di-O-acetyl-1,5-anhydro-2,6-dideoxy-L-arabino-hex-1-enitol (3,4-di-O-acetyl-L-rhamnal) (6) and 3,4-di-O-acetyl-1,5-anhydro-2,6-dideoxy-L-lyxo-hex-1-enitol (3,4-di-O-acetyl-L-fucal) (7) using N-iodosuccinimide gave the corresponding 7-O-glycosyl-β-rhodomycinones 8a,b, 9a,b and 10a,b, 11a,b. After cleavage of the THP-ether and O-deacetylation 7-O-(2,6-dideoxy-2-iodo-α-L-manno-hexopyranosyl)-β-rhodomycinone (14) and 7-O-(2,6-dideoxy-2-iodo-α-L-talo-hexopyranosyl)-β-rhodomycinone (16) were obtained.     

Synthesis of (5R*,6R*,7S*)-6-iodo-1,5,6,7-tetrahydro-4,1-benzoxazonin-3(2H)-ones

New 6-iodo-1,5,6,7-tetrahydro-3H-4,1-benzoxazonin-3-ones have been synthesized by reaction of N-tosyl- and N-(2-nitrobenzenesulfonyl)-N-[2-(alkenyl)phenyl]aminoacetic acids with molecular iodine.     

Reactions of N- and C-Alkenylanilines: V. Synthesis of Iodo-Substituted Heterocycles from o-Cycloalkenylanilines and Their Transformations

Iodination of N-isopropyl- and N-benzyl-2-(2-cyclohexenyl)anilines gave the corresponding 1-iodo-hexahydrocarbazoles which underwent quantitative isomerization into 3-iodo-2,4-propano-1,2,3,4-tetrahydro-quinolines. Nucleophilic substitution in 1-iodohexahydrocarbazoles and 3-iodo-2,4-propano-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole was studied. N-Allylation of the latter via reaction with allyl bromide is accompanied by replacement of the iodine atom by bromine.     

Synthesis of 1-iodo-1,2,3,4,4a,9a-hexahydrocarbazoles and their isomerization into 3-iodo-2,4-propano-1,2,3,4-tetrahydroquinolines

The reactions of 2-(cyclohex-2-enyl)-4,5-difluoroaniline or N-methyl-2-(cyclohex-2-enyl)aniline with I₂ in CCl₄ in the presence of NaHCO₃ give 1-iodo-1,2,3,4,4a,9a-hexahydrocarbazoles, which isomerize in MeCN into the corresponding 3-iodo-2,4-propano-1,2,3,4-tetrahydroquinolines in quantitative yields.     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

4-Oxa(thia)-9-oxa-2-azabicyclo[4.2.1]nonane-3-on(thion) derivatives

The synthesis of 7,8-dihydroxy-2-(2-methoxycarbonylethyl)-4,9-dioxa-2-azabicyclo[4.2.1]nonane- 3-thione ( 16 ) and of its parents 9-oxa-4-thia-3-thione 17 , and 9-oxa-4-thia-3-one 18 is described. The conversion of 5′-deoxy-5′-iodo-2′,3′-O, O-isopropylidene-5,6-dihydrouridin ( 1 ) into the 2-O-methyl-5,6-dihydrouridine 5 , the 5′-O-acetyl-5,6-dihydrouridine 4 , and into the N-(5-O-acetyl-2,3-O, O-isopropylidene-β-D -ribofuranosyl)-N-(2-methoxycarbonyl thyl)-urea ( 6 ) invoked 2′,3′-O, O-isopropylidene-2,5′-anhydro-5,6-dihydrouridine ( 2 ) as the common intermediate.     

Studies on the Base-Pairing Properties of N7-(2-Deoxy-β-D-erythro-pentofuranosyl)guanine (N7Gd)

The base-pairing properties of N⁷-(2-deoxy-β-D -erythro-pentofuranosyl)guanine (N⁷G_d; 1 ) are investigated. The nucleoside 1 was obtained by nucleobase-anion glycosylation. The glycosylation reaction of various 6-alkoxy-purin-2-amines 3a - i with 2-deoxy-3,5-di-O-(4-toluoyl)-α-D -erythro-pentofuranosyl chloride ( 8 ) was studied. The N⁹/N⁷-glycosylation ratio was found to be 1:1 when 6-isopropoxypurin-2-amine ( 3d ) was used, whereas 6-(2-methoxyethoxy)purin-2-arnine ( 3i ) gave mainly the N⁹-nucleoside (2:1). Oligonucleotides containing compound 1 were prepared by solid-phase synthesis and hybridized with complementary strands having the four conventional nucleosides located opposite to N⁷G_d. According to T_m values and enthalpy data of duplex formation, a base pair between N⁷G_d and dG is suggested. From the possible N⁷G_d dG base pair motives, Hoogsteen pairing can be excluded as 7-deaza-2′-deoxyguanosine forms the same stable base pair with N⁷G_d as dG.     

Pyrrolopyrimidine nucleosides. IV. The synthesis of certain 4,5-disubstituted-7-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines related to the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics

The treatment of 4-chloro-7-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 4 ) with N-bromoacetamide in methylene chloride has furnished the 5-bromo derivative of 4 which on subsequent deacetylation provided a good yield of 5-bromo-4-chloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d] pyrimidine ( 6 ). Assignment of the halogen substituent to position 5 was made on the basis of pmr studies. Treatment of 6 with methanolic ammonia afforded 4-amino-5-bromo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d ]pyrimidine ( 8 , 5-bromotubercidin) and a subsequent study has revealed that the 4-chloro group of 6 was replaced preferentially in a series of nucleophilic displacement reactions. The analogous synthesis of 4,5-dichloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d]pyrimidine ( 13b ) and 4-chloro-5-iodo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 13a ) from 4 furnished 5-chlorotubercidin ( 15 ) and 5-iodotubercidin ( 14 ), respectively, on treatment of 13b and 13a with methanolic ammonia. The possible biochemical significance of these tubercidin derivatives is discussed.     

The stereoselectivity of the alkylation of the dianion of ethyl 2-hydroxy-6-methylcyclohexanecarboxylates: Control of stereochemistry at three adjacent stereogenic centers

Yeast reduction of rac-ethyl 2-methyl-6-oxocylohexanecarboxylate (rac- 1 ) yielded selectively (+)-ethyl 2-hydroxy-6-methylcyclohexane carboxylate (+)- 2 (Scheme 1) which has been alkylated with 5-iodo-2-methylbut-2-ene by (the dianion method to furnish the 4-methylbut-3-enyl derivat 3 (Scheme 3)). NaBH₄ reduction of (+)- 1 led to three hydroxy-carboxylates (?)- 2 , (+)- 5 , and (?) -6 (Scheme 4). Allylation of the dianion of (+)- 5 afforded (+)- 7 .     

Ylides of heterocycles. VII.. I-, N-, P- and S-ylides of pyrimidones

The reaction of pyrimidone derivatives 1a-d with iodosobenzene prepared in situ from diacetoxyiodobenzene or dichloroiodobenzene afforded the iodonium-ylides 2a-d in good yields. Their thermal rearrangement produced 5-iodo-4-phenoxy-pyrimidin-6(1H)-ones 3a-c . Reductive deiodination of 3 gave the corresponding 4-phenoxypyrimidin-6(1H)-ones 4a-c . Acid catalized treatment of the iodonium-ylides 2a-d with nucleophiles such as pyridine, nicotinamide, isoquinoline, or triphenylphosphine produced the corresponding N- or P-ylides 7, 8, 9 , and 10 , respectively. The thiophanium-ylides 11a,c were obtained from the iodonium-ylides 2 without the use of a catalyst. The pyridinium-ylides 7 have been also prepared from the 5-halopyrimidones 5 or 6 which in turn could be obtained from the reactive iodonium-ylides 2 with hydrochloric or hydrobromic acid, respectively.     

Reaction of 3-Amino-2H-azirines with 2-Amino-4,6-dinitrophenol (Picramic Acid): Synthesis of Quinazoline- and 1,3-Benzoxazole Derivatives

The reaction of 3-(dimethylamino)-2H-azirines 1a–c and 2-amino-4,6-dinitrophenol (picramic acid, 2 ) in MeCN at 0° to room temperature leads to a mixture of the corresponding 1,2,3,4-tetrahydroquinazoline-2-one 5 , 3-(dimethylamino)-1,2-dihydroquinazoline 6 , 2-(1-aminoalkyl)-1,3-benzoxazole 7 , and N-[2-(dimethylamino)phenyl]-α-aminocarboxamide 8 (Scheme 3). Under the same conditions, 3-(N-methyl-N-phenyl-amino)-2H-azirines 1d and 1e react with 2 to give exclusively the 1,3-benzoxazole derivative 7 . The structure of the products has been established by X-ray crystallography. Two different reaction mechanisms for the formation of 7 are discussed in Scheme 6. Treatment of 7 with phenyl isocyanate, 4-nitrobenzoyl chloride, tosyl chloride, and HCl leads to a derivatization of the NH₂-group of 7 (Scheme 4). With NaOH or NaOMe as well as with morpholine, 7 is transformed into quinazoline derivatives 5 , 14 , and 15 , respectively, via ring expansion (Scheme 5). In case of the reaction with morpholine, a second product 16 , corresponding to structure 8 , is isolated. With these results, the reaction of 1 and 2 is interpreted as the primary formation of 7 , which, under the reaction conditions, reacts with Me₂NH to yield the secondary products 5 , 6 , and 8 (Scheme 7).     

Synthesis of 2′-Deoxyribofuranosides of 8-Aza-7-deazaguanine and Related Pyrazolo[3,4-d]pyrimidines

The N(1)- and N(2)-(2′-deoxyribofuranosides) 1 and 2 , respectively, of 8-aza-7-deazaguanine were prepared via phase-transfer glycosylation in the presence or absence of Bu₄NHSO₄ as catalyst of 6-amino-4-methoxy-lH-pyrazolo[3,4-d]pyrimidine ( 7c ) with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D -erythro-pentofuranosyl chloride ( 10 ). On a similar route, but without catalyst and employing THF as organic phase, the 6-amino-4-chloronucleosides 11b and 12b were synthesized from 7a and converted into the N(1)-and N(2)-substituted 4-thioxo analogues 17a and 18a , respectively. The ratio of N(1)- to N(2)-glycosylation was 2:1 for 7c and 1:1 for 7a , viz. depending on the nucleobase structure. The rate of the H⁺-catalyzed N-glycosyl hydrolysis was strongly decreased for the N(2)-(β-D -2′-deoxyribofuranosides) as compared to the N(1)-compounds. However, the N(1)-nucleoside 1 , which is an isostere of 2′-deoxyguanosine, is sufficiently stable to be employed later in solid-phase oligonucleotide synthesis.     

2′-Deoxy-β-D-ribofuranosides of N6-Methylated 7-Deazaadenine and 8-Aza-7-deazaadenine: Solid-phase synthesis of oligodeoxyribonucleotides and properties of self-complementary duplexes

The syntheses of 7-deaza-N⁶-methyladenine N⁹-(2′-deoxy-β-D -ribofuranoside) ( 2 ) as well as of 8-aza-7-deaza-N⁶-methyladenine N⁸? and N⁹?(2′-deoxyribofuranosides) ( 3 and 4 , resp.) are described. A 4,4′-dimeth-oxylritylation followed by phosphitylation yielded the methyl phosphoramidites 12–14 . They were employed together with the phosphoramidite of 2′-deoxy-N⁶v-methyladenosine ( 15 ) in automated solid-phase oligonucleotide synthesis. Alternating or palindromic oligonucleotides derived from d(A-T)₆ or d(A-T-G-C-A-G-A*-T-C-T-G-C-A) but containing one methylated pyrrolo[2,3-d]pyrimidine or pyrazolo[3,4-d]pyrimidine moiety in place of a N⁶-methylaminopurine (A*) were synthesized. Melting experiments showed that duplex destabilization induced by a N⁶-Me group of 2′-deoxy-N⁶-methyladenosine is reversed by incorporation of 8-aza-7-deaza-2′-deoxy-N⁶-meihyladenosine, whereas 7-deaza-2′-deoxy-N⁶-methyladenostne decreased the T_m value further. Regiospecific phosphodiester hydrolysis of d(A-T-G-C-A-G-m⁶A-T-C-T-G1-C-A) by the endodeoxyribonuclease Dpn I, yielding d(A-T-G-C-A-G-m⁶A) and d(pT-C-T-G-C-A), was prevented when the residue c⁷m⁶A_d ( 2 ), c⁷m⁶z⁸A_d ( 3 ), or c⁷m⁶z⁸A_d′ ( 4 ) replaced m⁶A_d ( 1 ) indicating that N(7) of N⁶-methyladenine is a proton-acceptor site for the endodeoxyribonuclease.